Synthetic method for preparing fluorine-containing biphenyl compound by one-pot method

Abstract

The invention discloses a synthesis method for preparing a fluorine-containing biphenyl compound by a one-pot method, which comprises the following steps: taking fluorine-containing bromobenzene 1A as an initial raw material, reacting with magnesium to generate fluorine-containing phenyl magnesium bromide, reacting with (RO) 3B, hydrolyzing to generate fluorine-containing aryl boric acid ester C, and carrying out coupled reaction with aryl chloride 2A to obtain a target product fluorine-containing biphenyl B; in the formula, R1 is H, F, C1-C6 alkyl and C1-C6 alkoxy; the R group is C1-C6 alkyl, and the R2 group is any one of H, F, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, nitryl, ester group and carbonyl. According to the method, fluorine-containing bromobenzene is used as a raw material, fluorine-containing phenyl magnesium bromide is prepared from fluorine-containing bromobenzene and magnesium, fluorine-containing phenyl magnesium bromide reacts with boric acid ester and is hydrolyzed to prepare fluorine-containing aryl boric acid ester, and aryl chloride is directly coupled to obtain a target product fluorine-containing biphenyl through a one-pot method without treatment; the method is simple and convenient, can be completed in one pot without post-treatment, and is high in yield and controllable in cost.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a one-pot method for preparing a fluorine-containing biphenyl compound. Background Art

[0002] Fluorinated biphenyls have important application value in the modern industrial field, especially in liquid crystal materials and fluorinated pesticide intermediates. In liquid crystal materials, fluorinated biphenyls can give the materials excellent properties such as good chemical stability, a wide operating temperature range, low viscosity and high charge retention. In the field of pesticides, fluorinated biphenyls, as intermediates, are essential for the synthesis of fluorinated pesticides.

[0003] At present, researchers have conducted a lot of research and exploration on the preparation methods of fluorinated biphenyls, mainly focusing on synthesizing target products through different chemical reactions and raw materials.

[0004] Method 1, a fluorine-containing aryl boronic acid and an aryl chloride coupling synthesis method (two-step method), the synthetic route (1-1) is as follows:

[0005]

[0006] As shown in route 1-1, fluorinated biphenyl is synthesized by coupling fluorinated aryl boronic acid and aryl chloride. This is a common two-step synthesis route. This method is commonly used in the preparation of fluorinated biphenyls containing active groups (R1 and / or R2 contain active groups, such as nitro, etc.), but there is a problem of low yield of synthesizing fluorinated aryl boronic acid, resulting in an increase in the total cost of the entire synthesis process, and low economic benefits in large-scale industrial production.

[0007] Method 2, using bis-pinacol borate one-pot method to synthesize polyfluorinated biphenyls, the synthesis routes (1-2, 1-3) are as follows:

[0008]

[0009] The method mentioned in patent CN105753644A is shown in route 1-2, which is to use fluorinated bromobenzene and bis-pinacol borate to prepare polyfluorinated biphenyls in one step. Its limitation is that it only limits the coupling of one substrate structure (1A), and cannot be widely applied to the synthesis of fluorinated biphenyls with different substrate structures, and its application range is relatively narrow.

[0010]

[0011] As shown in route 1-3, fluorine-containing bromobenzene (1A) is reacted with bis-pinacol borate to prepare fluorine-containing aryl pinacol borate, and then directly coupled with aryl chloride (2A) to prepare fluorine-containing biphenyl (B). However, there are two major problems in this method: first, the price of bis-pinacol borate is relatively high, which increases the cost of raw materials. Secondly, this method requires a two-step coupling reaction, which is relatively complicated to operate, resulting in low production efficiency and further increased cost, which is not conducive to large-scale production.

[0012] Method 3, fluorinated aryl Grignard reagent reacts with aryl chloride to prepare fluorinated biphenyl. For example, US 8211820B2 mentions a method for preparing fluorinated biphenyl, wherein the coupling catalyst uses Fe / Co salt catalyst, 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, etc. as ligands. The catalysts and ligands used in these methods are relatively expensive, which increases the production cost.

[0013] In summary, the existing methods for preparing fluorinated biphenyls all have defects to varying degrees, and have problems in terms of cost, substrate applicability, production efficiency, etc. Therefore, it is necessary to develop a new and more advantageous method for preparing fluorinated biphenyls to solve these problems. Summary of the invention

[0014] The purpose of the present invention is to provide a simple method for synthesizing a fluorinated biphenyl compound, which has cheap and readily available raw materials, mild reaction conditions, wide substrate applicability, high production efficiency and controllable costs.

[0015] In order to achieve the above object, the present invention provides a one-pot method for preparing a fluorinated biphenyl compound, the synthetic route is:

[0016]

[0017] The method comprises the following steps: using fluorine-containing bromobenzene 1A as a starting material, reacting with magnesium to prepare fluorine-containing phenyl magnesium bromide, reacting with (RO)3B, and then hydrolyzing to prepare fluorine-containing aromatic borate C, and coupling reaction with aromatic chloride 2A to obtain the target product fluorine-containing biphenyl B; wherein the R1 group is H, F, C1-C6 alkyl, C1-C6 alkoxy; the R group is C1-C6 alkyl; and the R2 group is at least one of H, F, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, nitro, ester, and carbonyl.

[0018] Optionally, the amount of magnesium and the fluorine-containing bromobenzene 1A used is (1-1.05):1 in a molar ratio.

[0019] Optionally, an initiator is also added, which can trigger a chemical reaction between fluorine-containing bromobenzene 1A and magnesium, and the initiator is at least one of iodine, ethyl bromide, ethyl iodide, and propylmagnesium bromide; the amount of the initiator and the fluorine-containing bromobenzene 1A is (0.001-0.01):1 in a molar ratio.

[0020] Optionally, (RO)3B is at least one of trimethyl borate, triethyl borate, tributyl borate, tripropyl borate, triisopropyl borate, and triisobutyl borate; the molar ratio of (RO)3B to fluorine-containing bromobenzene 1A is (1.05-1.3):1.

[0021] Optionally, the reaction temperature of fluorine-containing bromobenzene 1A and magnesium is 20-60° C., and the reaction time is 1-2 hours; the reaction temperature of fluorine-containing phenyl magnesium bromide and (RO) 3B is -5° C. to -20° C., and the reaction time is 2-4 hours.

[0022] Optionally, the amount of pure water used for hydrolysis to form the fluorine-containing aromatic borate ester C is 10-20 times that of the fluorine-containing bromobenzene, calculated on a substance basis.

[0023] Optionally, the molar ratio of the aromatic chloride 2A to the fluorine-containing bromobenzene 1A is (1-1.05):1.

[0024] Optionally, a dual catalyst is added as a catalyst for the coupling reaction, and the dual catalyst includes: the first catalyst and the second catalyst; wherein the first catalyst includes at least one of triphenylphosphine palladium chloride, tetrakistriphenylphosphine palladium, Pd2(dba)3, and 1,1'-bisdiphenylphosphinodiferrocene palladium dichloride; the amount of the first catalyst and fluorine-containing bromobenzene 1A is 0.005%-0.01% by mole percentage; the second catalyst includes at least one of palladium acetate and palladium trifluoroacetate, and the amount of the second catalyst and fluorine-containing bromobenzene 1A is 0.005%-0.01% by mole percentage.

[0025] Optionally, the second catalyst is used in combination with a Buchwald ligand (SPhos, JohnPhos, XPhos, DavePhos, RuPhos, BrettPhos), and the amount of the Buchwald ligand and the fluorine-containing bromobenzene 1A used is 0.01%-0.02% by mole percentage.

[0026] Optionally, a base is further added to the coupling reaction, and the molar ratio of the base to the fluorine-containing bromobenzene 1A is (1.8-2.5):1, and the base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium phosphate.

[0027] Compared with the prior art, the technical solution of the present invention has at least the following beneficial effects:

[0028] The invention is easy to operate. After the first use of Grignard reagent to prepare boric ester, no post-treatment is required, and the fluorinated biaryl hydrocarbon compound can be directly coupled with an aryl chloride to prepare the fluorinated biaryl hydrocarbon compound. The one-pot method is completed, the operation is simple, and the yield of the target product is as high as more than 90%. At the same time, the substrate active group has good tolerance and the substrate has wide applicability.

[0029] Furthermore, the present invention innovatively uses dual catalysts (a first catalyst and a second catalyst) and a ligand system to promote the coupling reaction, thereby greatly reducing the amount of catalyst used, increasing the reaction conversion rate to more than 90%, and greatly reducing the cost.

[0030] In addition, the raw materials and reagents of the present invention are relatively cheap and readily available, and the sources are stable, which further makes the cost low and controllable. DETAILED DESCRIPTION

[0031] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] The "C1-C6 alkyl" described herein refers to an alkyl group containing 1 to 6 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, n-hexyl and the like.

[0033] The "C1-C6 alkoxy" described herein refers to a group formed by combining an alkyl group having 1 to 6 carbon atoms and an oxygen atom, including methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

[0034] As described in the background technology, in the prior art, the synthesis of fluorinated biphenyl B is basically to use aryl boronic acid and chloro compound coupling, and its boric acid yield is low, and the cost is high, which reduces the advantage of the synthetic route reaction. And adopting Grignard reagent and chloro compound coupling method, catalyst and ligand costs are higher, and it is required that there can be no active functional group on the chloro compound, and the cost is high, and the scope of application is narrow. In addition, after using bis-pinacol borate to be prepared into fluorinated aryl pinacol borate, then in the method for preparing fluorinated biphenyl B by coupling with chloro compound, the raw material bis-pinacol borate unit price is up to 600 yuan / kg, and the cost is higher, which is not conducive to amplification production.

[0035] The present invention provides a one-pot method for preparing a fluorinated biphenyl compound, and the synthetic route is:

[0036]

[0037] Wherein, fluorine-containing bromobenzene 1A is used as a starting material, and is prepared with magnesium to form fluorine-containing phenyl magnesium bromide, which is then reacted with (RO)3B and hydrolyzed to form fluorine-containing aryl borate C, which is coupled with aryl chloride 2A to obtain the target product fluorine-containing biphenyl B; wherein the R1 group is any one of H, F, C1-C6 alkyl, and C1-C6 alkoxy; and the R group is C1-C6 alkyl. The R2 group in the coupled aryl chloride 2A of the present invention can be an inert group, for example, H, F, C1-C6 alkyl, C1-C6 alkoxy, etc., or can be an active group containing hydroxyl, nitro, ester, carbonyl, etc. that can react with Grignard reagents, so the present invention has a wide range of applications. In this article, R, R1 and R2 can be the same or different.

[0038] In some embodiments, the molar ratio of magnesium to fluorine-containing bromobenzene 1A is (1-1.05):1.

[0039] In some embodiments, an initiator is further added, and the initiator can initiate a chemical reaction between fluorine-containing bromobenzene 1A and magnesium. The initiator is at least one of iodine, ethyl bromide, ethyl iodide, and propylmagnesium bromide; the amount of the initiator and the fluorine-containing bromobenzene 1A is (0.001-0.01):1 in a molar ratio.

[0040] In some embodiments, (RO)3B is at least one of trimethyl borate, triethyl borate, tributyl borate, tripropyl borate, triisopropyl borate, and triisobutyl borate; and the molar ratio of (RO)3B to fluorine-containing bromobenzene 1A is (1.05-1.3): 1. (RO)3B is preferably trimethyl borate because of its low molecular weight and low price.

[0041] In some embodiments, the reaction temperature of fluorine-containing bromobenzene 1A and magnesium is 20-60°C, and the reaction time is 1-2 hours; the reaction temperature of fluorine-containing phenyl magnesium bromide and (RO)3B is -5°C to -20°C, and the reaction time is 2-4 hours. The reaction solvent can be tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, tetrahydrofuran / toluene mixed solvent, etc.; toluene / tetrahydrofuran with lower cost is preferred; the amount of solvent used is 2-5 times the weight of fluorine-containing bromobenzene.

[0042] In some embodiments, the amount of pure water used for hydrolysis to form the fluorine-containing aromatic borate ester C is 10-20 times that of the fluorine-containing bromobenzene, calculated on a substance basis.

[0043] In some embodiments, the molar ratio of the aromatic chloride 2A to the fluorine-containing bromobenzene 1A is (1-1.05):1.

[0044] In some embodiments, a dual catalyst is added as a catalyst for the coupling reaction, and the dual catalyst includes: the first catalyst and the second catalyst; wherein the first catalyst includes at least one of triphenylphosphine palladium chloride, tetrakistriphenylphosphine palladium, Pd2(dba)3, and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, preferably triphenylphosphine palladium chloride; the amount of the first catalyst and fluorine-containing bromobenzene (1A) is 0.005%-0.01% by mole percentage; the second catalyst includes at least one of palladium acetate and palladium trifluoroacetate, and the amount of the second catalyst and fluorine-containing bromobenzene 1A is 0.005%-0.01% by mole percentage.

[0045] In some embodiments, the second catalyst is used in combination with a Buchwald (SPhos, JohnPhos, XPhos, DavePhos, RuPhos, BrettPhos) ligand, and the amount of the Buchwald ligand and the fluorine-containing bromobenzene 1A used is 0.01%-0.02% by mole percentage. Palladium acetate and SPhos ligand are preferred.

[0046] In some embodiments, a base is further added to the coupling reaction, and the molar ratio of the base to the fluorine-containing bromobenzene 1A is (1.8-2.5):1, and the base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium phosphate. In some embodiments, the base needs to be prepared into a concentration of 20wt%-30wt% using pure water as a solvent.

[0047] In some embodiments, the coupling reaction temperature is 80° C. to 90° C. The coupling reaction solvent can be selected from toluene, benzene, tetrahydrofuran, dioxane, any one or two thereof; the amount of the solvent is 1-2 times the weight ratio of the fluorine-containing bromobenzene.

[0048] The specific steps are as follows:

[0049] First, add 1-2 times the weight of fluorine-containing bromobenzene, tetrahydrofuran and magnesium into the reaction container, stir and heat to 55°C-60°C under nitrogen protection, add 0.01-0.05 amount (molar number) of initiator (iodine, etc.) of fluorine-containing bromobenzene, control the temperature to 55°C-60°C, initiate the reaction, then control the temperature to 20°C-60°C, add dropwise fluorine-containing bromobenzene toluene solution (toluene dosage: 1-3 times the weight of fluorine-containing bromobenzene), after the dropwise addition, the temperature is between 20°C-65°C, keep warm for 2 hours, then cool to 20°C-35°C, and the Grignard reaction solution is ready for use.

[0050] In another reaction container, add 1.05-1.3 times the amount (molar number) of borate ester and 1-2 times the weight of fluorine-containing bromobenzene toluene. After the addition, cool down to -5°C to -20°C under nitrogen protection, and add the prepared Grignard reaction solution dropwise. After the addition is completed, the mixture is kept at -5°C to -20°C for 2 hours, and then pure water in an amount (molar number) of 10-20 times the amount of fluorine-containing bromobenzene is added thereto for hydrolysis to form fluorine-containing aromatic borate (C). Then, toluene in an amount of 1-2 times the weight ratio of fluorine-containing bromobenzene and a pure aqueous solution of 20% to 30% of alkali are added to the reaction container. After the addition is completed, catalyst 1 in an amount (molar number) of 0.005-0.01% of fluorine-containing bromobenzene, catalyst 2 in an amount (molar number) of 0.005-0.01% of fluorine-containing bromobenzene, and Buchwald ligand in an amount (molar number) of 0.01-0.02% of fluorine-containing bromobenzene are added under nitrogen protection while stirring. The mixture is heated to 80°C to 90°C while stirring, reacted for 4 hours, cooled to 20°C to 35°C, separated, the organic layer is washed with water until neutral, passed through a silica gel column, concentrated, crystallized, and dried to obtain the target product fluorine-containing biphenyl B.

[0051] The following is a description of the specific examples. In this example, unless otherwise specified, the raw materials and solvents used are all commercially available.

[0052] Example

[0053] First, add 100g of tetrahydrofuran and 12.6g of magnesium (0.525mol) to a 500ml glass three-necked flask, under nitrogen protection, stir and heat to 55℃~60℃, add 0.13g of iodine (0.0005mol), control the temperature to 55℃~60℃ to initiate the reaction, then control the temperature to 30℃~35℃ and drop 96.5g (0.5mol) of 3,4-difluorobromobenzene (in 1A, R1 is H) and 100g of toluene mixed solution, add it in about 1 hour, and keep it at 30℃~35℃ after dropping. Keep it warm for 2 hours until the magnesium is basically reacted, then cool it to 20℃~35℃, and the Grignard reaction solution is ready for use.

[0054] In another 1500ml glass three-necked flask, add 57.2g (0.55mol) trimethyl borate and 100g toluene. After the addition, cool down to -10℃~-15℃ under nitrogen protection, and drop the prepared Grignard reaction solution. After about 1 hour of dropwise addition, keep at -10℃~-15℃ for 2 hours, drop 90g (5mol) of pure water to hydrolyze to form 3,4-difluorophenyl boric acid dimethyl ester (in C, R1 is H), then add 78.8g (0.5mol) of 2-nitrochlorobenzene (in 2A, R2 is nitro) and 100g of toluene to the flask, and after the addition, add 353g 30% sodium carbonate pure water solution (sodium carbonate 106g and 247g pure water solution), after adding, add 0.018g (0.000025mol) bis(triphenylphosphine)palladium dichloride, 0.012 (0.000053mol) palladium acetate, 0.041g (0.0001mol) 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl under nitrogen protection, after adding, under nitrogen protection, heat to 80-90°C with stirring, react for 4h, cool to 20-35°C, separate, add 100g water to the organic layer each time, wash until neutral, pass through a 10g silica gel column, concentrate, crystallize with petroleum ether, and dry to obtain 105.8g 2-nitro-3'-4'-difluorobiphenyl, with a yield of 90%.

[0055] In summary, the present invention uses fluorine-containing bromobenzene as a raw material, first reacts with magnesium to prepare fluorine-containing phenyl magnesium bromide, then reacts with boric acid ester, and then hydrolyzes to prepare fluorine-containing aryl boric acid ester. No treatment is required, and aromatic chloride is directly coupled under the promotion of dual catalysts to obtain the target product fluorine-containing biphenyl. The method is simple, does not require post-treatment, can be completed in one pot, and the yield is as high as more than 90%.

[0056] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be appreciated that the above description should not be considered as a limitation of the present invention. After reading the above content, it will be apparent to those skilled in the art that various modifications and substitutions of the present invention will occur. Therefore, the protection scope of the present invention should be limited by the appended claims.

Claims

1. A one-pot method for preparing a fluorinated biphenyl compound, characterized in that: The synthetic route is: The method comprises the following steps: using fluorine-containing bromobenzene (1A) as a starting material, reacting with magnesium to generate fluorine-containing phenylmagnesium bromide, and then reacting with (RO)3B, and then hydrolyzing to generate fluorine-containing aromatic borate (C), and then coupling reaction with aromatic chloride (2A) to obtain the target product fluorine-containing biphenyl (B); wherein the R1 group is any one of H, F, C1-C6 alkyl, and C1-C6 alkoxy; the R group is C1-C6 alkyl; and the R2 group is any one of H, F, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, nitro, ester, and carbonyl.

2. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: The amount of magnesium and the fluorine-containing bromobenzene (1A) used is (1-1.05):1 in molar ratio.

3. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: An initiator is also added, and the initiator can initiate a chemical reaction between the fluorine-containing bromobenzene (1A) and magnesium. The initiator is at least one of iodine, ethyl bromide, ethyl iodide, and propylmagnesium bromide. The amount of the initiator and the fluorine-containing bromobenzene (1A) is in a molar ratio of (0.001-0.01):

1.

4. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: (RO)3B is at least one of trimethyl borate, triethyl borate, tributyl borate, tripropyl borate, triisopropyl borate, and triisobutyl borate; the molar ratio of (RO)3B to fluorine-containing bromobenzene (1A) is (1.05-1.3):

1.

5. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: The reaction temperature of fluorine-containing bromobenzene (1A) and magnesium is 20°C to 60°C, and the reaction time is 1 to 2 hours; the reaction temperature of fluorine-containing phenyl magnesium bromide and (RO)3B is -5°C to -20°C, and the reaction time is 2 to 4 hours.

6. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: The amount of pure water used for the hydrolysis to form the fluorine-containing aromatic borate (C) is 10-20 times that of the fluorine-containing bromobenzene, calculated on the amount of substance.

7. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: The molar ratio of the aromatic chloride (2A) to the fluorine-containing bromobenzene (1A) is (1-1.05):

1.

8. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: A dual catalyst is also added as a catalyst for the coupling reaction, and the dual catalyst comprises: the first catalyst and the second catalyst; wherein the first catalyst comprises at least one of triphenylphosphine palladium chloride, tetrakistriphenylphosphine palladium, Pd2(dba)3, and 1,1'-bisdiphenylphosphinodiferrocene palladium dichloride; the amount of the first catalyst and the fluorine-containing bromobenzene (1A) is 0.005%-0.01% in molar percentage; the second catalyst comprises at least one of palladium acetate and palladium trifluoroacetate, and the amount of the second catalyst and the fluorine-containing bromobenzene (1A) is 0.005%-0.01% in molar percentage.

9. The one-pot method for preparing a fluorinated biphenyl compound according to claim 8, characterized in that: The second catalyst is used in combination with a Buchwald ligand, and the amount of the Buchwald ligand and the fluorine-containing bromobenzene (1A) used is 0.01%-0.02% in molar percentage.

10. The one-pot method for preparing a fluorinated biphenyl compound according to claim 1, characterized in that: A base is also added in the coupling reaction, and the molar ratio of the base to the fluorine-containing bromobenzene (1A) is (1.8-2.5):

1. The base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium phosphate.

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